The innate immune system is the first line of defense against infection. It also initiates and directs the proper function of the adaptive immune response, the other branch of the immune system. The crucial importance of the innate immune system has been long utilized in vaccination and more recently reflected by the studies of the pattern recognition receptors and the ensuing signaling pathways at a near frenzy pace. Despite the rapid progress of the field, the critical standing questions of the molecular mechanisms underlying innate immune recognition and signal transduction remain unanswered. This project is focused on the detailed mechanisms underlying the initiation of innate immune responses by the receptors. This program integrates functional studies with extensive structural analysis of membrane bound (such as the Toll-like receptors) and cytoplasmic (such as RIG-I and NOD2) pattern recognition receptors in complex with their ligands as well as downstream adapters and effector molecules. A critical feature of these innate immune receptors is that they distinguish among various classes of molecules characteristic of pathogens while retaining a capacity for responsiveness to a large number of related structures within a given biochemical class. How the binding domains of the innate receptors achieve such ?broad? reactivity at the atomic level is one of the key issues this project addresses. Such information could be used to guide the development of new therapeutics that can either enhance or limit immune activation involving these receptors. Ligand binding by these receptors in turn initiates intracellular signaling cascades that ultimately lead to innate cellular responses that help fight infection and also guide the activities of other limbs of the immune system. The project aims to decipher this signaling network through studying protein-protein interactions, using X-ray crystallography in conjunction with other biophysical and biochemical techniques. The ultimate goal is to not only delineate the mechanisms of innate immune responses at atomic details and contribute to our general understanding of signal transduction, but also to lay a foundation for future clinical exploitation of the innate immune system for human benefit.